Development of thyroxine type II deiodinase activity in brains of Zucker rats

The present study was undertaken to determine whether the capacity for 3,5,3′,5′-tetraiodothyronine (T4) conversion into 3,5,3′-tri-iodothyronine (T3), as measured by the activity of thyroxine type II 5′-monodeiodinase (T4-5′D), was altered in the brains of young Zucker fa/fa rats during the period of intense maturation of the central nervous system (i.e. from 10 to 20 days of life). From 7 to 14 days of age, no difference in brain T4-5′D activity could be detected between lean and pre-obese rats; serum free T4 was not affected by the fa gene. During the suckling to weaning transition, T4-5′D reached a plateau in brains of lean rats, while it increased by 50% in brains of pre-obese rats; concurrently, serum free T4 increased in Fa/fa rats, whereas it did not change in fa/fa rats. The increased capacity for conversion of T4 into T3 observed in brains of pre-obese compared with lean rats could not be ascribed to a variation in the amount of T4-5′D, since Vmax. did not differ between the two genotypes; however, it could be totally accounted for by an increased affinity of the enzyme for T4. This change may represent an adaptive response to low serum free T4 in order to maintain the cerebral T3 concentration in pre-obese rats. These results show that the alteration in T4 metabolism in brains of fa/fa rats is not an early event and thus cannot interfere with maturation of the central nervous system. However, the decreased serum free T4 which was observed in pre-obese rats after suckling might play a secondary role in development of this genetic obesity.

Thyroxine action on the rat liver nuclear thyroid-hormone receptors. Binding of thyroxine to the nuclear non-histone protein and induction of mitochondrial alpha-glycerophosphate dehydrogenase activity

The possibility that thyroxine (T4) itself exerts the hormonal effect in vivo on the rat liver nuclear receptor was studied with the aid of iopanoic acid (IOP), an inhibitor of the conversion of T4 into tri-iodothyronine (T3). After administration of 2.4 micrograms of T4/100 g body weight to hypothyroid rats for 7 days, T4 and T3 concentrations in serum and in the liver nuclear non-histone protein (NHP) were all increased to the hyperthyroid range. Hepatic mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) activity and DNA content increased significantly. The equilibrium association constant (Ka) of the nuclear T3 receptor was unchanged and the maximal binding capacity (Cmax.) increased 1.4-fold. Simultaneous administration of IOP (5 mg/100 g body weight) to the rats given 2.4 micrograms of T4/100 g body weight completely blocked the conversion into T3. The serum T4 was even more increased, whereas the serum T3 decreased to the hypothyroid range. Although the NHP-bound T4 was at a concentration comparable with the rats given T4 alone, no NHP-bound T3 was detected. Yet the alpha-GPD activity was elevated 2.8-fold and the DNA content increased to the same extent as observed in the rats given T4 alone. The Ka and Cmax. of the nuclear receptor were significantly decreased. After administration of 48 or 480 micrograms of T4/100 g body weight for 3 days, serum T4 and T3 were markedly increased. The NHP-bound T3 was also increased, but no NHP-bound T4 was detected. The alpha-GPD activity was markedly elevated, but the DNA content was unchanged. The Cmax. per g of liver was increased, whereas the Ka remained unchanged. Simultaneous administration of IOP to these animals could not completely block the T4 conversion. The observed hormonal effects in the absence of nuclear T3 indicate that T4 possesses the intrinsic hormonal activities on the rat liver. T4 is less potent in induction of alpha-GPD activity but as potent in increment of hepatic DNA as T3. Although the binding site for T4 is not fully characterized, it appears to be acidic NHP. T4 is an active hormone, yet is also a prohormone of T3, offering the closest analogy with testosterone.